A Novel Five-Step Route to the Synthesis of Psilocin from Indole-3-carbaldehyde

Masanori Somei,* Fumio Yamada, and Mayumi Tamura

Although considerable efforts1,2 have been devoted to
the syntheses of psilocin1 (1),
psilocybin1 (2), and their analogs, there still
remains to establish structure-activity relationships. With a hope to
find a lead compound among psilocin analogs possesing suitable
pharmacological effects for psychotic diseases such as depression,
schizophrenia, Alzheimer's disease, and so on, we have developed a
novel five-step preparative method of 1 from
indole-3-carbaldehyde (3).

>We have already reported one pot procedure3 for
preparing 4-benzyloxyindole-3-carbaldehyde (4) from 3.
The overall yield of 4, however, did not exceed 58% and varied
depending on the reaction conditions. The one pot procedure consists
of three reactions: 1) regioselective thallation of the 4-position of
3, 2) transformation of C-Tl bond to C-I bond, and 3)
conversion of the C-I bond to C-OCH2Ph bond.

We have attempted to improve the yield of 4 as well as the
reproducibility in order to utilize the one pot procedure as the
first step in the preparative method of 1. Among the three
reactions involved, we thoroughly reexamined the third reaction of
4-iodoindole-3-carbaldehyde (5) with metal benzyloxide (20-26
mol eq) in the presence of CuI (3 mol eq) in DMF at
1200C.3 Consequently, we found that not only
the preparation method of metal benzyloxide but also the metal itself
is an important factor for controlling the overall yield. Thus,
treatment of 5 with sodium benzyloxide (NaOCH2Ph),
prepared from sodium and benzyl alcohol (PhCH2OH),
afforded 4 in 24% yield. When NaH was employed to produce
NaOCH2Ph, the yield doubled to 48%. In contrast, when
potassium was used instead of sodium, further improvement in the
yield was observed (54%). Finally, KH was found to be the reagent of
choice and thereby the yield was raised up to 70%. Among the tested
solvents, DMF was found to give the best yield of 4.
Replacement of DMF by either HMPA or PhCH2OH dropped the
yield to 48 or 30%, respectively. We have further reconfirmed that
the suitable amount of KOCH2Ph is 25 mol eq to the
starting material 3.

The other important factor to keep reproducibility in the one pot
procedure was the relative ratio of iodination reagents
(I2 and CuI) to KOCH2Ph. Fixing the amount of
KOCH2Ph to about 25 mol eq, the ratio was examined
culminating in finding that 3.0 mol eq to 3 was the best
reaction conditions, where the desired 4 was produced in 72%
overall yield from 3 with an excellent reproducibility.

As the second step in the preparative method of 1, 4
was transformed into 4-benzyloxyindole-3-acetonitrile (6) in
89% yield utilizing our reaction,4 thus by treating
4 with NaBH4 in the presence of NaCN in MeOH and
formamide. Reduction of 6 with LiAlH4 in
Et2O is the third step giving the known
4-benzyloxytryptamine1a (7) in 96% yield.
Interestingly, when THF was used as a solvent instead of
Et2O, the yield of 7 decreased dramatically to the
range of 25 to 46%. As the fourth step, dimethylation of 7 was
carried out with formaldehyde and sodium cyanoborohydride5
in AcOH to produce 81c in 97% yield. The final step
of debenzylation of 8 was the catalytic hydrogenation using
10% Pd/C producing psilocin1d (1) in 84% yield.
Since 1 was converted to psilocybin (2) in two steps by
Hofman and co-workers,1c the present method constitutes a
seven-step synthesis of 2 as well.

In conclusion, we could establish a novel five-step preparative
method of 1 in 50% overall yield and 50% originality
rate.6 Utilizing 1 and its intermediates (4,
6-8), the syntheses of psilocin analogs and particularly the
compounds having substituents in the benzene part are in progress.